Agonists of a2a adenosine receptors for treating recurrent tumor growth in the liver following resection

ABSTRACT

The present invention relates to a method for treating recurrent tumor metastases following liver resection that includes administration of an effective amount of an agonist of A 2A  adenosine receptors (ARs).

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims the priority benefits of U.S. ProvisionalApplication No. 60/925,736, filed Apr. 23, 2007, which is expresslyincorporated fully herein by reference.

FIELD OF THE INVENTION

The present invention relates to a method for treating recurrent tumormetastases following liver resection that includes administration of aneffective amount of an agonist of A_(2A) adenosine receptors (ARs).

BACKGROUND OF THE INVENTION

In the United States, approximately 150,000 patients are diagnosed withcolorectal cancer each year. About 20% of these patients have metastaticdeposits of colorectal cancer in the liver only at the time of diagnosisor develop such metastases during the course of their illness. In theabsence of treatment, the prognosis for patients with hepatic colorectalmetastases is dismal, with 5-year survival rates of 3% or less. There isnow evidence that resection of such metastases can improve theprognosis. Although liver resection is not the primary treatment formost patients with hepatic colorectal metastases, appropriate liverresection is the standard of care for treatment of patients withisolated hepatic colorectal metastases. The majority of patientsexperience recurrence following hepatic resection of colorectalmetastases. Patients at high risk for recurrence after hepatic resectionare those who present with multiple hepatic metastases (vs. singlemetastases), large metastatic tumors (>5 cm), a high CEA serumconcentration (>200 ng/mL), a node-positive primary colorectal cancer,or synchronous tumors (primary colorectal cancer and hepatic colorectalmetastases). A treatment that reduced or eliminated recurrence afterhepatic resection would be highly desirable.

The notion that tissue inflammation and tumor growth are intricatelyassociated phenomena is relatively old, but the cell types and signalingintermediates that define this interrelationship are only beginning tobe identified, as are the potential targets for therapeuticintervention. Most studies have focused on elucidating how chronicinflammation promotes the progression of pre-malignant to malignantlesions. Previous work has shown that the outgrowth of late stage tumors(colorectal liver metastases) is stimulated by inflammation and necrosisof liver tissue following ischemia/reperfusion (I/R)(see Hepatology2005, 42, 165-175; and, Br. J. Surg. 2006, 93, 1015-1022).Unfortunately, the mechanisms underlying the accelerated outgrowth ofinflammation-associated late-stage metastatic tumors are unknown. Thus,the development of an effective treatment that suppressessurgery-induced inflammation-associated tumor growth is desirable.

SUMMARY OF THE INVENTION

The present invention provides a novel method for treating recurrenttumor metastases following liver resection comprising administering to apatient in need thereof a therapeutically effective amount of an A_(2A)adenosine receptor agonist or a pharmaceutically acceptable saltthereof.

The present invention also provides pharmaceutical compositionscomprising an A_(2A) receptor agonist or a pharmaceutically acceptablesalt thereof effective to treat recurrent tumor metastases followingliver resection and a pharmaceutically acceptable excipient.

The present invention provides a compound of the present invention or apharmaceutically acceptable salt thereof for use in medical therapy.

The present invention also provides the use of a compound of the presentinvention or a pharmaceutically acceptable salt thereof for themanufacture of a medicament for the treatment of recurrent tumormetastases following liver resection.

These and other objects, which will become apparent during the followingdetailed description, have been achieved by the inventors' discoverythat an agonist of an A_(2A) receptor can be used to treat recurrenttumor metastases following liver resection.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated herein and form a partof the specification, illustrate some aspects of the present inventionand together with the description, serve to explain the principles ofthe invention.

FIG. 1. Micrometasases were induced as described in paragraph 00242.Mice were subjected to left lobar I/R and were treated with ATL313 orvehicle as described in section 00242. Five days after the operation(day 10 of the exp) the mice were sacrificed; the livers were harvestedand stained using haematoxylin and eosin. Areas of normal liver tissue(dark pink), tumor tissue (t, purple) and necrosis (m, light pink) caneasily be discriminated. The figure shows that ATL treatment preventstissue necrosis and necrosis-associated tumor growth.

FIG. 2. This figure shows quantifications of the area of liver tissuethat has been replaced by tumor tissue (Hepatic Replacement Area (HRA)in sham-operated mice, in I/R-subjected mice, and in I/R-subjected micetreated with ATL or ZM. White bars correspond to HRA values measured inthe (non-clamped) right and median liver lobes. The black barscorrespond to HRA values measured in the left (clamped) lobes.

FIG. 3. This figure shows quantifications of the area of liver tissuethat has been replaced by necrotic tissue in sham-operated mice, inI/R-subjected mice (left lobe), and in I/R-subjected mice treated withATL or ZM. White bars correspond to necrosis values measured in the(non-clamped) right and median liver lobes. The black bars correspond tonecrosis values measured in the left (clamped) lobes.

FIG. 4: This figure shows the ratio of hepatic replacement area (HRA)values in ischemic (clamped) left liver lobes versus non-ischeme rightand median liver lobes. In sham-operated mice this ratio isapproximately 1. The percentage tumor area in the left lobes is equal tothat in the right and median lobes. However, in I/R subjected mice tumorgrowth in the clamped (left lobes) is approximately 2.5-fold higher thanthat in the non-clamped (right and median) lobes. ATL treatment preventsthe increase in tumor growth in the left (clamped) liver lobes andthereby normalizes the ratio between tumor growth in the left andright/median lobes to 1. ZM, which inactivates the A_(2A)R, appears toaggravate tumor growth in the clamped liver lobes, thereby increasingthe left-to-right/median ratio, although this difference did not reachstatistical significance.

DETAILED DESCRIPTION OF THE INVENTION

A mouse model has been developed in which selective temporary occlusionof blood flow into the left liver lobe results in a profoundacceleration of tumor growth in the clamped, but not in the unclampedliver lobes. Accelerated tumor growth is closely associated with tissuenecrosis and inflammation. Administration of the immune suppressantATL313, an adenosine A_(2A) receptor agonist, almost completelyprevented tissue necrosis, inflammation, and accelerated tumor growthfollowing I/R (see FIG. 1). The results of these studies show thatadministration of an A_(2A) receptor agonist (e.g., ATL-313) isefficacious in reducing tumor metastases following liver resection.

In light of this discovery, the present invention provides a novelmethod for treating recurrent tumor metastases following liverresection, comprising: administering to a patient in need thereof atherapeutically effective amount of an A_(2A) adenosine receptoragonist. The agonist can be administered prior to resection, duringresection, following resection, and a combination thereof.

Examples of agonists of A_(2A) adenosine receptors that are expected touseful in the practice of the present invention include compounds havingthe formula I or a stereoisomer or pharmaceutically acceptable saltthereof:

wherein

Z^(a) is C≡C, O, NH, or NHN═CR^(3a);

Z is CR³R⁴R⁵ or NR⁴R⁵;

each R¹ is independently hydrogen, halo, —OR^(a), —SR^(a), (C₁-C₈)alkyl,cyano, nitro, trifluoromethyl, trifluoromethoxy, (C₃-C₈)cycloalkyl,heterocycle, heterocycle(C₁-C₈)alkylene-, aryl, aryl(C₁-C₈)alkylene-,heteroaryl, heteroaryl(C₁-C₈)alkylene-, —CO₂R^(a), R^(a)C(═O)O—,R^(a)C(═O)—, —OCO₂R^(a), R^(b)R^(c)NC(═O(O)O—, R^(a)OC(═O)N(R^(b))—,R^(b)R^(c)N—, R^(b)R^(c)NC(═O)—, R^(a)C(═O)N(R^(b))—,R^(b)R^(c)NC(═O)N(R^(b))—, R^(b)R^(c)NC(═S)N(R^(b))—, —OPO₃R^(a),R^(a)OC(═S)—, R^(a)C(═S)—, —SSR^(a), R^(a)S(═O)—, R^(a)S(═O)₂—, or—N═NR^(b);

each R² is independently hydrogen, halo, (C₁-C₈)alkyl,(C₃-C₈)cycloalkyl, heterocycle, heterocycle(C₁-C₈)alkylene-, aryl,aryl(C₁-C₈)alkylene-, heteroaryl, or heteroaryl(C₁-C₈)alkylene-;

alternatively, R⁴ and R⁵ and the atom to which they are attached is C═O,C═S or C═NR^(d),

R⁴ and R⁵ are independently H or (C₁-C₈)alkyl;

alternatively, R⁴ and R⁵ together with the atom to which they areattached form a saturated, partially unsaturated, or aromatic ring thatis mono-, bi- or polycyclic and has 3, 4, 5, 6, 7, 8, 9 or 10 ring atomsoptionally having 1, 2, 3, or 4 heteroatoms selected from non-peroxideoxy (—O—), thio (—S—), sulfinyl (—SO—), sulfonyl (—S(O)₂—) or amine(—NR^(b)—) in the ring;

wherein R⁴ and R⁵ are independently substituted with 0-3 R⁶ groups orany ring comprising R⁴ and R⁵ is substituted with from 0 to 6 R⁶ groups;

each R⁶ is independently hydrogen, halo, —OR^(a), —SR^(a), (C₁-C₈)alkyl,cyano, nitro, trifluoromethyl, trifluoromethoxy, (C₁-C₈)cycloalkyl,(C₆-C₁₂)bicycloalkyl, heterocycle, heterocycle (C₁-C₈)alkylene-, aryl,aryl (C₁-C₈)alkylene-, heteroaryl, heteroaryl(C₁-C₈)alkylene-,—CO₂R^(a), R^(a)C(═O)O—, R^(a)C(═O)—, —OCO₂R^(a), R^(b)R^(c)NC(═O)O—,R^(a)OC(═O)N(R^(b))—, R^(b)R^(c)N—, R^(b)R^(c)NC(═O)—,R^(a)C(═O)N(R^(b))—, R^(b)R^(c)NC(═O)N(R^(b))—,R^(b)R^(c)NC(═S)N(R^(b))—, —OPO₃R^(a), R^(a)OC(═S)—, R^(a)C(═S)—,—SSR^(a), R^(a)S(═O)—, —NNR^(b), or two R⁶ groups and the atom to whichthey are attached is C═O, C═S; or two R⁶ groups together with the atomor atoms to which they are attached can form a carbocyclic orheterocyclic ring comprising from 1-6 carbon atoms and 1, 2, 3, or 4heteroatoms selected from non-peroxide oxy (—O—), thio (—S—), sulfinyl(—SO—), sulfonyl (—S(O)₂—) or amine (—NR^(b)—) in the ring;

R³ is hydrogen, halo, —OR^(a), —SR^(a), (C₁-C₈)alkyl, cyano, nitro,trifluoromethyl, trifluoromethoxy, (C₃-C₈)cycloalkyl, heterocycle,heterocycle(C₁-C₈)alkylene-, aryl, aryl(C₁-C₈)alkylene-, heteroaryl,heteroaryl(C₁-C₈)alkylene-, —CO₂R^(a), R^(a)C(═O)O—, R^(a)C(═O)—,—OCO₂R^(a), R^(b)R^(c)NC(═O)O—, R^(a)OC(═O)N(R^(b))—, R^(b)R^(c)N—,R^(b)R^(c)NC(═O)—, R^(a)C(═O)N(R^(b))—, R^(b)R^(c)NC(═O)N(R^(b))—,R^(b)R^(c)NC(═S)N(R^(b))—, —OPO₃R^(a), R^(a)OC(═S)—, R^(a)C(═S)—,—SSR^(a), R^(a)S(═O)—, R^(a)S(═O)₂—, —NNR^(b); or if the ring formedfrom CR⁴R⁵ is aryl or heteroaryl or partially unsaturated then R³ can beabsent;

R^(3a) is hydrogen, (C₁-C₈)alkyl, or aryl;

each R⁷ is independently hydrogen, (C₁-C₈)alkyl, (C₃-C₈)cycloalkyl,aryl, aryl(C₁-C₈)alkylene, heteroaryl, or heteroaryl(C₁-C₈)alkylene-;

X is —CH₂OR^(a), —CO₂R^(a), —CH₂OC(O)R^(a), —C(O)NR^(b)R^(c),—CH₂SR^(a), —C(S)OR^(a), —CH₂OC(S)R^(a), —C(S)NR^(b)R^(c), or—CH₂N(R^(b))(R^(c));

alternatively, X is an aromatic ring of the formula:

each Z¹ is non-peroxide oxy (—O—), S(O)₀₋₂, —C(R⁸)—, or amine (—NR⁸—),provided that at least one Z¹ is non-peroxide oxy (—O—), thio (—S—),sulfinyl (—SO—), sulfonyl (—S(O)₂—) or amine (—NR⁸—);

each R⁸ is independently hydrogen, (C₁-C₈)alkyl, (C₁-C₈)alkenyl,(C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₈)alkylene,(C₃-C₈)cycloalkenyl, (C₃-C₈)cycloalkenyl(C₁-C₈)alkylene, aryl,aryl(C₁-C₈)alkylene, heteroaryl, or heteroaryl(C₁-C₈)alkylene, whereinany of the alkyl or alkenyl groups of R⁸ are optionally interrupted by—O—, —S—, or —N(R^(a))—;

wherein any of the alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl,groups of R¹, R², R³, R^(3a), R⁶, R⁷ and R⁸ is optionally substituted oncarbon with one or more (e.g. 1, 2, 3, or 4) substituents selected fromthe group consisting of halo, —OR^(a), —SR^(a), (C₁-C₈)alkyl, cyano,nitro, trifluoromethyl, trifluoromethoxy, (C₃-C₈)cycloalkyl,(C₆-C₁₂)bicycloalkyl, heterocycle, heterocycle(C₁-C₈)alkylene-, aryl,aryloxy, aryl(C₁-C₈)alkylene-, heteroaryl, heteroaryl(C₁-C₈)alkylene-,—CO₂R^(a), R^(a)C(═O)O—, R^(a)C(═O)—, —OCO₂R^(a), R^(b)R^(c)NC(═O)O—,R^(a)OC(═O)N(R^(b))—, R^(b)R^(c)N—, R^(b)R^(c)NC(═O)—,R^(a)C(═O)N(R^(b))—, R^(b)R^(c)NC(═O)N(R^(b))—,R^(b)R^(c)NC(═S)N(R^(b))—, —OPO₃R^(a), R^(a)OC(═S)—, R^(a)C(═S)—,—SSR^(a), R^(a)S(═O)_(p)—, R^(b)R^(c)NS(O)_(p)—, and —N═NR^(b);

wherein any (C₁-C₈)alkyl, (C₃-C₈)cycloalkyl, (C₆-C₁₂)bicycloalkyl,(C₁-C₈)alkoxy, (C₁-C₈)alkanoyl, (C₁-C₈)alkylene, or heterocycle, isoptionally partially unsaturated;

each R^(a), R^(b) and R^(c) is independently hydrogen, (C₁-C₁₂)alkyl,(C₁-C₈)alkoxy, (C₁-C₈)alkoxy-(C₁-C₁₂)alkylene, (C₃-C₈)cycloalkyl,(C₃-C₈)cycloalkyl-(C₁-C₁₂)alkylene, (C₁-C₈)alkylthio, amino acid, aryl,aryl(C₁-C₈)alkylene, heterocycle, heterocycle-(C₁-C₈)alkylene,heteroaryl, or heteroaryl(C₁-C₈)alkylene;

alternatively R^(b) and R^(c), together with the nitrogen to which theyare attached, form a pyrrolidino, piperidino, morpholino, orthiomorpholino ring;

wherein any of the alkyl, cycloalkyl, heterocycle, aryl, or heteroarylgroups of R^(a), R^(b) and R^(c) is optionally substituted on carbonwith 1 or 2 substituents selected from the group consisting of halo,—(CH₂)_(a)OR^(e), —(CH₂)_(a)SR^(e), (C₁-C₈)alkyl, (CH₂)_(a)CN,(CH₂)_(a)NO₂, trifluoromethyl, trifluoromethoxy, —(CH₂)_(a)CO₂R³,(CH₂)_(a)NR^(e)R^(e), and (CH₂)_(a)C(O)NR^(e)R^(e);

R^(d) is hydrogen or (C₁-C₆)alkyl;

R^(e) is independently selected from H and (C₁-C₆)alkyl;

a is 0, 1, or 2;

i is 1 or 2

m is 0 to 8; and

p is 0 to 2;

provided that m is at least 1 when Z is NR⁴R⁵; or

a pharmaceutically acceptable salt thereof.

Specific values listed below for radicals, substituents, and ranges, arefor illustration only; they do not exclude other defined values or othervalues within defined ranges for the radicals and substituents.

For example, specific values include compounds having the formula (Ia):

wherein

R¹ is hydrogen, —OH, —CH₂OH, —OMe, —OAc, —NH₂, —NHMe, —NMe₂ or —NHAc;

R² is hydrogen, (C₁-C₈)alkyl, cyclopropyl, cyclohexyl or benzyl;

R³ is hydrogen, OH, OMe, OAc, NH₂, NHMe, NMe₂ or NHAc;

CR⁴R⁵ or NR⁴R⁵ is optionally substituted with 0-2 R⁶ groups and iscyclopentane, cyclohexane, piperidine, dihydro-pyridine,tetrahydro-pyridine, pyridine, piperazine, tetrahydro-pyrazine,dihydro-pyrazine, pyrazine, dihydro-pyrimidine, tetrahydro-pyrimidine,hexahydro-pyrimidine, pyrazine, imidazole, dihydro-imidazole,imidazolidine, pyrazole, dihydro-pyrazole, and pyrazolidine;

alternatively, the ring CR⁴R⁵ or NR⁴R⁵ is optionally substituted with0-4 (e.g., 0 to 2) R⁶ groups and is selected from the group consistingof:

R⁶ is hydrogen, (C₁-C₈)alkyl, —OR^(a), —CO₂R^(a), R^(a)C(═O)—,R^(a)C(═O)O—, R^(b)R^(c)N—, R^(b)R^(c)NC(═O)—, or aryl;

R^(a), R^(b) and R^(c) are independently hydrogen, (C₃-C₄)-cycloalkyl,(C₁-C₈)alkyl, aryl or aryl(C₁-C₈)alkylene;

each R⁷ is independently hydrogen, alkyl (e.g., C₁-C₈alkyl), aryl,aryl(C₁-C₈)alkylene or heteroaryl(C₁-C₈)alkylene;

R⁸ is methyl, ethyl, propyl, 2-propenyl, cyclopropyl, cyclobutyl,cyclopropylmethyl, —(CH₂)₂CO₂CH₃, or —(CH₂)₂₋₃OH;

X is —CH₂OR^(a), —CO₂R^(a), —CH₂OC(O)R^(a), or —C(O)NR^(b)R^(c);

alternatively X is selected from:

m is 0, 1 or 2;

or a pharmaceutically acceptable salt thereof.

Additional specific values include compounds having the formula (Ia),wherein:

R¹ is hydrogen, OH, OMe, or NH₂;

R² is hydrogen, methyl, ethyl or propyl;

R³ is hydrogen, OH, OMe, or NH₂;

the ring CR⁴R⁵ or NR⁴R⁵ is selected from the group consisting of:

where q is from 0 to 4 (e.g., 0-2);

R⁶ is hydrogen, (C₁-C₈)alkyl, —OR^(a), —CO₂R^(a), R^(a)C(═O)—,R^(a)C(═O)O—, R^(b)R^(c)N—, R^(b)R^(c)NC(═O)—, or aryl;

R^(a) and R^(b) are independently hydrogen, methyl, ethyl, propyl,butyl, ethylhexyl, cyclopropyl, cyclobutyl, phenyl or benzyl;

N(R⁷)₂ is amino, methylamino, dimethylamino; ethylamino; pentylamino,diphenylethylamino, (pyridinylmethyl)amino, (pyridinyl)(methyl)amino,diethylamino or benzylamino; and,

R⁸ is methyl, ethyl, propyl, or cyclopropyl;

X is —CH₂OR^(a) or —C(O)NR^(b)R^(c);

alternatively, X is selected from:

or a pharmaceutically acceptable salt thereof.

Additional specific values include compounds having the formula (Ia),wherein:

R¹ is hydrogen, OH, or NH₂;

R² is hydrogen or methyl;

R³ is hydrogen, OH, or NH₂;

the ring CR⁴R⁵ or NR⁴R⁵ is selected from the group consisting of:

where q is from 0 to 2;

R⁶ is hydrogen, methyl, ethyl, t-butyl, phenyl, —CO₂R^(a)—CONR^(b)R^(c),or R^(c)C(═O)—;

R^(b) is H;

R^(a) is methyl, ethyl, propyl, butyl, pentyl, ethylhexyl cyclopropyl,and cyclobutyl;

—N(R⁷)₂ is amino, methylamino, dimethylamino; ethylamino; diethylaminoor benzylamino;

or a pharmaceutically acceptable salt thereof.

Additional specific values include compounds having the formula (Ia),wherein:

R¹ is hydrogen or OH;

R² is hydrogen;

R³ is hydrogen or OH;

the ring CR⁴R⁵ or NR⁴R⁵ is selected from the group consisting of:

R⁶ is hydrogen, methyl, ethyl, —CO₂R^(a), and —CONR^(b)R^(c);

R^(b) is H;

R^(a) is methyl, ethyl, i-propyl, i-butyl, tert-butyl, and cyclopropyl;

N(R⁷)₂ is amino, or methylamino;

X is —CH₂OH,

C(O)NHCH₃, or —C(O)NHCH₂CH₃;

or a pharmaceutically acceptable salt thereof.

Additional specific values include compounds wherein: the ringcomprising R⁴, R⁵ and the atom to which they are connected is 2-methylcyclohexane, 2,2-dimethylcyclohexane, 2-phenylcyclohexane,2-ethylcyclohexane, 2,2-diethylcyclohexane, 2-tert-butyl cyclohexane,3-methyl cyclohexane, 3,3-dimethylcyclohexane, 4-methyl cyclohexane,4-ethylcyclohexane, 4-phenyl cyclohexane, 4-tert-butyl cyclohexane,4-carboxymethyl cyclohexane, 4-carboxyethyl cyclohexane,3,3,5,5-tetramethyl cyclohexane, 2,4-dimethyl cyclopentane,4-cyclohexanecarboxylic acid, 4-cyclohexanecarboxylic acid esters,4-methyloxyalkanoyl-cyclohexane, 4-piperidine-1-carboxylic acid methylester, 4-piperidine-1-carboxylic acid tert-butyl ester 4-piperidine,4-piperazine-1-carboxylic acid methyl ester, 4-piperidine-1-carboxylicacid tert-butylester, 1-piperidine-4-carboxylic acid methyl ester,1-piperidine-4-carboxylic acid tert-butyl ester, tert-butylester,1-piperidine-4-carboxylic acid methyl ester, or1-piperidine-4-carboxylic acid tert-butyl ester,3-piperidine-1-carboxylic acid methyl ester, 3-piperidine-1-carboxylicacid tert-butyl ester, 3-piperidine, 3-piperazine-1-carboxylic acidmethyl ester, 3-piperidine-1-carboxylic acid tert-butylester,1-piperidine-3-carboxylic acid methyl ester, or1-piperidine-3-carboxylic acid tert-butyl ester; or a pharmaceuticallyacceptable salt thereof.

Additional specific values include compounds having the formula (Ia),

R¹ is hydrogen or OH;

R² is hydrogen;

R³ is hydrogen or OH;

the ring CR⁴R⁵ or NR⁴R⁵ is selected from the group consisting of:

R⁶ is —CO₂R^(a);

R^(a) is (C₁-C₈)alkoxy, (C₃-C₆)cycloalkyl,(C₃-C₆)cycloalkyl-(C₁-C₃)alkylene, heterocycle, andheterocycle-(C₁-C₃)alkylene;

wherein any of the alkyl, cycloalkyl, heterocycle, aryl, or heteroarylgroups of R^(a), R^(b) and R^(c) is optionally substituted on carbonwith 1 or 2 substituents selected from the group consisting of halo,OR^(e), (C₁-C₄)alkyl, —CN, NO₂, trifluoromethyl, trifluoromethoxy,CO₂R³, NR^(e)R^(e), and C(O)NR^(e)R^(e); and,

R^(e) is independently selected from H and (C₁-C₄)alkyl.

Exemplary compounds from that are expected to be useful in the presentinvention are shown in Table A below.

TABLE A

Ex. # R^(c) R⁷ —(R¹)_(m)—Z 1. Et H

2. Et H

3. cPr H

4. Et H

5. cPr H

6. Et H

7. cPr H

8. Et H

9. Et H

10. Et H

11. Et H

12. cPr H

13. Et H

14. cPr H

15. Et H

16. cPr H

17. cPr H

18. Et H

19. cPr H

20. Et H

21. cPr H

22. Et H

23. Et H

24. cPr H

25. Et H

26. Et H

27. Et H

28. Et H

29. Et H

30. Et H

31. cPr H

32. Et H

33. Et H

34. cPr H

35. cPr H

36. Et H

37. cPr H

38. Et H

39. cPr H

40. Et H

41. cPr H

42. Et H

* signifies the point of attachment.

Further examples of agonists of A_(2A) adenosine receptors that areexpected to useful in the practice of the present invention includecompounds having the formula II or a stereoisomer or pharmaceuticallyacceptable salt thereof:

wherein:

R¹ and R² independently are selected from the group consisting of H,(C₁-C₈)alkyl, (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₈)alkylene, aryl,aryl(C₁-C₈)alkylene, heteroaryl, heteroaryl(C₁-C₈)alkylene-,diaryl(C₁-C₈)alkylene, and diheteroaryl(C₁-C₈)alkylene, wherein the aryland heteroaryl rings are optionally substituted with 1-4 groupsindependently selected from fluoro, chloro, iodo, bromo, methyl,trifluoromethyl, and methoxy;

each R independently is selected from the group consisting of H, C₁-C₄alkyl, cyclopropyl, cyclobutyl, and (CH₂)_(a)cyclopropyl;

X is CH or N, provided that when X is CH then Z cannot be substitutedwith halogen, C₁-C₆ alkyl, hydroxyl, amino, or mono- ordi-(C₁-C₆-alkyl)amino;

Y is selected from the group consisting of O, NR¹, —(OCH₂CH₂O)_(m)CH₂—,and —(NR¹CH₂CH₂O)_(m)CH₂—, provided that when Y is O or NR¹, then atleast one substituent is present on Z;

Z is selected from the group consisting of 5-membered heteroaryl,6-membered aryl, 6-membered heteroaryl, carbocyclic biaryl, andheterocyclic biaryl, wherein the point of attachment of Y to Z is acarbon atom on Z, wherein Z is substituted with 0-4 groups independentlyselected from the group consisting of F, Cl, Br, I, (C₁-C₄)alkyl,—(CH₂)_(a)OR³, —(CH₂)_(a)NR³R³, —NHOH, —NR³NR³R³, nitro, —(CH₂)_(a)CN,(CH₂)_(a)CO₂R³, —(CH₂)_(a)CONR³R³, trifluoromethyl, andtrifluoromethoxy;

alternatively, Y and Z together form an indolyl, indolinyl,isoindolinyl, tetrahydroisoquinolinyl, or tetrahydroquinolinyl moietywherein the point of attachment is via the ring nitrogen and whereinsaid indolyl, indolinyl, isoindolinyl, tetrahydroisoquinolinyl, ortetrahydroquinolinyl moiety, which is substituted with 0-4 groupsindependently selected from the group consisting of F, Cl, Br, I, C₁-C₄alkyl, —(CH₂)_(a)OR³, —(CH₂)_(a)NR³R³, —NHOH, —NR³NR³R³, NO₂,—(CH₂)_(a)CN, —(CH₂)_(a)CO₂R³, —(CH₂)_(a)CONR³R³, CF₃, and OCF₃;

R³ is independently selected from the group consisting of H,(C₁-C₆)alkyl, cycloalkyl, aryl, and heteroaryl;

R⁴ is selected from the group consisting of CH₂OR, C(O)NRR, and CO₂R;

R⁵ is selected from the group consisting of CH₂CH₂, CH═CH, and C≡C;

a is selected from 0, 1, and 2;

m is selected from 1, 2, and 3;

n is selected from 0, 1, and 2;

each p independently is selected from 0, 1, and 2; and,

q is selected from 0, 1, and 2.

Additional specific values include compounds having the formula IIa or apharmaceutically acceptable salt thereof:

Additional specific values include compounds having the formula Ib or apharmaceutically acceptable salt thereof:

wherein:

each Z′ is independently selected from the group consisting F, Cl, Br,I, C₁-C₄alkyl, —(CH₂)_(a)OR³, —(CH₂)_(a)NR³R³, —NHOH, —NR³NR³R³, NO₂,—(CH₂)_(a)CN, —(CH₂)_(a)CO₂R³, —(CH₂)_(a)CONR³R³, CF₃, and OCF₃.

Additional specific values include compounds wherein R is selected fromH, methyl, ethyl or cyclopropyl.

Additional specific values include compounds having the formula IIc or apharmaceutically acceptable salt thereof:

Additional specific values include compounds wherein Z′ is selected fromthe group consisting of F, Cl, methyl, OR³, NO₂, CN, NR³R³ and CO₂R³.

Additional specific values include compounds wherein R³ is methyl orhydrogen.

Additional exemplary compounds that are expected to be useful in thepresent invention are shown in Table B below.

TABLE B i

ii

iii

R⁴=A: CH₂OH; B: C(O)NEthyl; C: C(O)NCyclopropyl.

Compounds are of formula (i), unless indicated.

Ex. # R⁴ Z′  1 C

 2 C

 3 C

 4 A

 5 C

 6 A

 7 A

 8 C

 9 C

10 C

11 A

12 A

13 A

14 C

15 B

16 B

17 C

18 C

19 B

20 C

21 C

22 C

23 C

24 B

25 B

26 B

27 A

28 A

29 A

30 A

31 B

32 B

33 B

34 B

35 A

36 A

37(iii) B

38(iii) C

39(iii) C

40(iii) C

41(iii) C

42 C

43(ii) C

44(ii) A

45(ii) A

46(ii) A

47(ii) C

48(ii) C

49 B

50 B

51 C

52 C

53 A

54 A

55 A

56 C

57 C

Additional specific values include compounds having the formula(Ib)-(Id) or a pharmaceutically acceptable salt thereof:

Additional examples of A_(2A) adenosine receptor agonists that areexpected to be useful in the present invention include compounds offormula 4:

wherein R^(a) is methyl, ethyl, propyl, isopropyl, isobutyl, or t-butyl.

Additional examples of A_(2A) adenosine receptor agonists that areexpected to be useful in the present invention include those describedin U.S. Pat. No. 6,232,297 and in U.S. Patent Application No.2003/0186926 A1.

Further examples of compounds expected to be useful in the presentinvention include formula (IA)

In formula (IA) n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, or 18. In another group of specific compounds n is, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18.

Additional examples of A_(2A) adenosine receptor agonists that areexpected to be the present invention include compounds of the inventioninclude formula (IB)

In formula (IB) k is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, or 18.

Additional examples of A_(2A) adenosine receptor agonists that areexpected to be useful in the present invention include compounds of theinvention include formula (IC)

wherein 1 is 0, 1, 2, 3, or 4.

Other specific compounds of the invention include

Additional examples of compounds expected to useful in the presentinvention are illustrated in tables 1, 2, and 3 below:

TABLE 1

Compound R R¹ R² R⁶ ATL2037 NECA H H CH₂OH MP9056 NECA OH H CH₂OHATL146a NECA H H CO₂H MP9057 NECA OH H CO₂H ATL146e NECA H H CO₂MeMP9058 NECA OH H CO₂Me JR2145 CH₂OH H H CO₂Me MP9059 CH₂OH OH H CO₂MeATL193 NECA H H CH₂OAc MP9060 NECA OH H CH₂OAc JR2147 CH₂OH H H CH₂OAcMP9061 CH₂OH OH H CH₂OAc JR3023 NECA H H CH₂N(CH₃)₂ MP9062 NECA OH HCH₂N(CH₃)₂ JR3021 NECA H H COOCH₂CH₂NHBoc MP9063 NECA OH HCOOCH₂CH₂NHBoc JR3033 NECA H H COOCH₂CH₂NH₂ MP9064 NECA OH HCOOCH₂CH₂NH₂ JR3037 NECA H H CONHCH₂CH₃ MP9065 NECA OH H CONHCH₂CH₃JR3055 NECA H H CONH₂ MP9072 NECA OH H CONH₂ JR3065 NECA H H CONHMeMP9066 NECA OH H CONHMe JR3067B NECA H H Me, cis CO₂Me MP9067 NECA OH HMe, cis CO₂Me JR3067A NECA H H Me, trans CO₂Me MP9068 NECA OH H Me,trans CO₂Me JR3087 NECA H H CH₂CH₃ MP9069 NECA OH H CH₂CH₃ JR3159A NECAOH H H JR3159B NECA OH H H JR3119 NECA H H COCH₃ MP9070 NECA OH H COCH₃JR3121 NECA H H CHCH₃(OH) MP9071 NECA OH H CHCH₃(OH) JR3139 NECA OHC₆H₁₁ H NECA = CH₃CH₂N(H)C(O)—

TABLE 2

Compound R¹ R² R⁶ JR3261 H H H JR3259 H H CO₂tBu JR3269 H H CO₂Et JR4011H H CO₂iBu JR4009 H H CO₂iPr JR4007 H H COMe JR4051 H H COC(CH₃)₃ JR4047H H COCH₂(CH₃)₃ MP9047 H H COCH₃ MP9048 H H C(O)N(CH₃)₂ MP9049 H HC(O)N(CH₃)Et MP9050 H H C(O)N(CH₃)iPr MP9051 H H C(O)N(CH₃)iBu MP9052 HH C(O)NH(CH₃) MP9053 H H C(O)NH(Et) MP9054 H H C(O)NH(iPr) MP9055 H HC(O)NH(iBu) TX3261 OH H H TX3259 OH H CO₂tBu TX3269 OH H CO₂Et TX4011 OHH CO₂iBu TX4009 OH H CO₂iPr TX4007 OH H COMe TX4051 OH H COC(CH₃)₃TX4047 OH H COCH₂(CH₃)₃ TX9047 OH H COCH₃ TX9048 OH H C(O)N(CH₃)₂ TX9049OH H C(O)N(CH₃)Et TX9050 OH H C(O)N(CH₃)iPr TX9051 OH H C(O)N(CH₃)iBuTX9052 OH H C(O)NH(CH₃) TX9053 OH H C(O)NH(Et) TX9054 OH H C(O)NH(iPr)TX9055 OH H C(O)NH(iBu)

TABLE 3

Compound n R³ R⁶ JR3135 1 OH H JR3089 2 OH H JR3205 2 NH₂ H JR3177A 2 OH2-CH₃ JR3177B 2 OH 2-CH₃ JR3181A 2 OH 2-CH₃ JR3181B 2 OH 2-CH₃ JR3227 2OH 2-C(CH₃)₃ JR9876 2 OH 2-C₆H₅ JR3179 2 OH 3-CH₃ JR3221 2 OH (R) 3-CH₃(R) ATL 203 2 OH (S) 3-CH₃ (R) MP9041 2 OH (R) 3-CH₃ (S) MP9042 2 OH (S)3-CH₃ (S) JR3201B 2 OH 3-(CH₃)₂ MP9043 2 OH (R) 3-CH₂CH₃ (R) MP9044 2 OH(S) 3-CH₂CH₃ (R) MP9045 2 OH (R) 3-CH₂CH₃ (S) MP9046 2 OH (S) 3-CH₂CH₃(S) JR3163 2 OH 3-(CH₃)₂, 5-(CH₃)₂ JR9875 2 OH 4-CH₃ JR3149 2 OH 4-C₂H₅JR3203 2 OH 4-C(CH₃)₃ JR3161 2 OH 4-C₆H₅

Additional examples of A_(2A) adenosine receptor agonists that areexpected to be useful in the present invention include compounds offormula (II):

wherein Z is CR³R⁴R⁵; each R¹, R² and R³ is hydrogen; R⁴ and R⁵ togetherwith the carbon atom to which they are attached form a cycloalkyl ringhaving 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms; and

wherein the ring comprising R⁴ and R⁵ is substituted with —(CH₂)₀₋₆—Y;where Y is —CH₂OR^(a), —CO₂R^(a), —OC(O)R^(a), —CH₂OC(O)R^(a),—C(O)NR^(b)R^(c), —CH₂SR^(a), —C(S)OR^(a), —OC(S)R^(a), —CH₂OC(S)R^(a)or C(S)NR^(b)R^(c) or —CH₂N(R^(b))(R^(c));

each R⁷ is independently hydrogen, (C₁-C₈)alkyl, (C₃-C₈)cycloalkyl, arylor aryl(C₁-C₈)alkylene;

X is —CH₂OR^(a), —CO₂R^(a), —CH₂OC(O)R^(a), —C(O)NR^(b)R^(c),—CH₂SR^(a), —C(S)OR^(a), —CH₂OC(S)R^(a), C(S)NR^(b)R^(c) or—CH₂N(R^(b))(R^(c));

each R^(a), R^(b) and R^(c) is independently hydrogen, (C₁-C₈)alkyl, or(C₁-C₈)alkyl substituted with 1-3 (C₁-C₈)alkoxy, (C₃-C₈)cycloalkyl,(C₁-C₈)alkylthio, amino acid, aryl, aryl(C₁-C₈)alkylene, heteroaryl, orheteroaryl(C₁-C₈)alkylene; or R^(b) and R^(c), together with thenitrogen to which they are attached, form a pyrrolidino, piperidino,morpholino, or thiomorpholino ring; and m is 0 to about 6; or apharmaceutically acceptable salt thereof.

A specific value for —N(R⁷)₂ is amino, monomethylamino orcyclopropylamino.

A specific value for Z is carboxy- or—(C₁-C₄)alkoxycarbonyl-cyclohexyl(C₁-C₄)alkyl.

A specific value for R^(a) is H or (C₁-C₄)alkyl, i.e., methyl or ethyl.

A specific value for R^(b) is H, methyl or phenyl.

A specific value for R^(c) is H, methyl or phenyl.

A specific value for —(CR¹R²)_(m)— is —CH₂— or —CH₂—CH₂—.

A specific value for X is CO₂R^(a), (C₂-C₅)alkanoylmethyl or amido.

A specific value for Y is CO₂R^(a), (C₂-C₅)alkanoylmethyl or amido.

A specific value for m is 1.

Specific compounds expected to be useful for practicing the inventionare compounds JR3259, JR3269, JR4011, JR4009, JR-1085 and JR4007.

Specific A_(2A) adenosine receptor agonists expected to be useful in thepresent invention having formula (II) include those described in U.S.Pat. No. 6,232,297.

Specific compounds of formula (II) are those wherein each R⁷ is H, X isethylaminocarbonyl and Z is 4-carboxycyclohexylmethyl (DWH-146a), Z is4-methoxycarbonylcyclohexylmethyl (DWH-146e), Z is4-isopropylcarbonylcyclohexylmethyl (AB-1), Z is4-acetoxymethyl-cyclohexylmethyl (JMR-193) or Z is4-pyrrolidine-1-carbonylcyclohexylmethyl (AB-3).

Additional examples of A_(2A) adenosine receptor agonists that areexpected to be useful in the present invention include those depictedbelow.

Additional examples of A_(2A) adenosine receptor agonists of formula(II) that are expected to be useful in the present invention includethose described in U.S. Pat. No. 6,232,297. These compounds, havingformula (II), can be prepared according to the methods describedtherein.

Another specific group of agonists of A_(2A) adenosine receptors thatare expected to be useful in the practice of the present inventioninclude compounds having the general formula (III):

wherein Z² is a group selected from the group consisting of —OR¹²,—NR¹³R¹⁴, a —C/C-Z³, and —NH—N═R¹⁷;

each Y² is individually H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, phenyl orphenyl C₁-C₃ alkyl;

R¹² is C₁₋₄-alkyl; C₁₋₄-alkyl substituted with one or more C₁₋₄-alkoxygroups, halogens (fluorine, chlorine or bromine), hydroxy groups, aminogroups, mono(C₁₋₄-alkyl)amino groups, di(C₁₋₄-alkyl)amino groups orC₆₋₁₀-aryl groups wherein the aryl groups may be substituted with one ormore halogens (fluorine, chlorine or bromine), C₁₋₄-alkyl groups,hydroxy groups, amino groups, mono(C₁₋₄-alkyl)amino groups ordi(C₁₋₄-alkyl)amino groups); or C₆₋₁₀-aryl; or C₆₋₁₀-aryl substitutedwith one or more halogens (fluorine, chlorine or bromine), hydroxygroups, amino groups, mono(C₁₋₄-alkyl)amino groups, di(C₁₋₄-alkyl)aminogroups or C₁₋₄-alkyl groups;

one of R¹³ and R¹⁴ has the same meaning as R¹² and the other ishydrogen; and

R¹⁷ is a group having the formula (I)

wherein each of R¹⁵ and R¹⁶ independently may be hydrogen,(C₃-C₇)cycloalkyl or any of the meanings of R¹², provided that R¹⁵ andR¹⁶ are not both hydrogen;

X² is CH₂OH, CH₃, CO₂R²⁰ or C(═O)NR²¹R²² wherein R²⁰ has the samemeaning as R¹³ and wherein R²¹ and R²² have the same meanings as R¹⁵ andR¹⁶ or R²¹ and R²² are both H;

Z³ has one of the following meanings:

C₆-C₁₀ aryl, optionally substituted with one to three halogen atoms,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₂-C₆alkoxycarbonyl, C₂-C₆ alkoxyalkyl, C₁-C₆ alkylthio, thio, CHO,cyanomethyl, nitro, cyano, hydroxy, carboxy, C₂-C₆ acyl, amino C₁-C₃monoalkylamino, C₂-C₆ dialkylamino, methylenedioxy or aminocarbonyl;

a group of formula —(CH₂)_(q)-Het wherein q is 0 or an integer from 1 to3 and Het is 5 or 6 membered heterocyclic aromatic or non-aromatic ring,optionally benzocondensed, containing 1 to 3 heteroatoms selected fromnon-peroxide oxygen, nitrogen or sulphur, linked through a carbon atomor through a nitrogen atom;

C₃-C₇ cycloalkyl optionally containing unsaturation or C₂-C₄ alkenyl;

wherein

R²³ is hydrogen, methyl or phenyl;

R²⁴ is hydrogen, C₁-C₆ linear or branched alkyl, C₅-C₆ cycloalkyl orC₃-C₇ cycloalkenyl, phenyl-C₁-C₂-alkyl or R²³ and R²⁴, taken together,form a 5 or 6-membered carbocyclic ring or R²⁵ is hydrogen and R²³ andR²⁴, taken together, form an oxo group or a corresponding acetalicderivative;

R²⁵ is OH, NH₂ dialkylamino, halogen, cyano; and n is 0 or 1 to 4; orC₁-C₁₆ alkyl, optionally comprising 1-2 double bonds, O, S or NY²;

or a pharmaceutically acceptable salt thereof.

Specific C₆₋₁₀-aryl groups include phenyl and naphthyl.

Additional specific values include compounds wherein in the compound offormula (III), Z² is a group of the formula (iii)

—O—(CH₂)_(n)—Ar  (iii)

wherein n is an integer from 1-4, e.g., 2, and Ar is a phenyl group,tolyl group, group, xylyl group or mesityl group. In one embodiment, Aris a para-tolyl group and n=2.

Additional specific values include compounds wherein in the compound offormula (III), Z² is a group of the formula (iv)

NHN═CHCy  (iv)

wherein Cy is a C₃₋₇-cycloalkyl group, such as cyclohexyl or a C₁₋₄alkyl group, such as isopropyl.

Additional specific values include compounds wherein in the compound offormula (III), Z² is a group of the formula (vii)

C≡CZ³  (v)

wherein Z³ is C₃-C₁₆ alkyl, hydroxy C₂-C₆ alkyl or(phenyl)(hydroxymethyl).

Additional examples of compounds of formula (III) include those shownbelow:

wherein the H on CH₂OH can optionally be replaced by ethylaminocarbonyl.Of these specific examples, WRC-0474-[SHA 211] and WRC-0470 areparticularly preferred.

Such compounds may be synthesized as described in: Olsson et al. (U.S.Pat. Nos. 5,140,015 and 5,278,150); Cristalli (U.S. Pat. No. 5,593,975);Miyasaka et al. (U.S. Pat. No. 4,956,345); Hutchinson, A. J. et al., J.Pharmacol. Exp. Ther., 251, 47 (1989); Olsson, R. A. et al., J. Med.Chem., 29, 1683 (1986); Bridges, A. J. et al., J. Med. Chem., 31, 1282(1988); Hutchinson, A. J. et al., J. Med. Chem., 33, 1919 (1990);Ukeeda, M. et al., J. Med. Chem., 34, 1334 (1991); Francis, J. E. etal., J. Med. Chem. 34, 2570 (1991); Yoneyama, F. et al., Eur. J.Pharmacol., 213, 199-204 (1992); Peet, N. P. et al., J. Med. Chem., 35,3263 (1992); and Cristalli, G. et al., J. Med. Chem., 35, 2363 (1992);all of which are incorporated herein by reference.

Additional specific values include compounds having formula (III) whereZ² is a group having formula (vi):

wherein R³⁴ and R³⁵ are independently H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl,phenyl, phenyl C₁-C₃ alkyl or R³⁴ and R³⁵ taken together with thenitrogen atom are a 5- or 6-membered heterocyclic ring containing 1-2heteroatoms selected from non-peroxide oxygen, nitrogen (N(R¹³)) orsulphur atoms. In one embodiment, one of R³⁴ and R³⁵ is hydrogen and theother is ethyl, methyl or propyl. In another embodiment, one of R³⁴ andR³⁵ is hydrogen and the other is ethyl or methyl.

A specific pyrazole derivative that is expected to be useful inpracticing the present invention is a compound having the formula:

Another specific group of agonists of A_(2A) adenosine receptors thatare expected to be useful in the present invention include compoundshaving the general formula (IV):

wherein Z⁴ is —NR²⁸R²⁹;

R²⁸ is hydrogen or (C₁-C₄)alkyl; and R²⁹ is

-   -   a) (C₁-C₄)alkyl;    -   b) (C₁-C₄)alkyl substituted with one or more (C₁-C₄) alkoxy,        halogen, hydroxy, amino, mono((C₁-C₄)alkyl)amino,        di((C₁-C₄)alkyl)amino or (C₆-C₁₀)aryl wherein aryl is optionally        substituted with one or more halogen, hydroxy, amino,        (C₁-C₄)alkyl, R³⁰OOC—((C₁-C₄)alkyl)-,        R³¹R³²NC(═O)—((C₁-C₄)alkyl)-, mono((C₁-C₄)alkyl)amino or        di((C₁-C₄)alkyl)amino;    -   c) (C₆-C₁₀)aryl; or    -   d) (C₆-C₁₀)aryl substituted with one or more halogen, hydroxy,        amino, mono((C₁-C₄)alkyl)amino, di((C₁-C₄)alkyl)amino or        (C₁-C₄)alkyl;

wherein each Y⁴ is individually H, (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl,phenyl or phenyl(C₁-C₃)alkyl; and X⁴ is —C(═O)NR³¹R³², —COOR³⁰, or—CH₂OR³⁰;

wherein each of R³¹ and R³² are independently; hydrogen;C₃₋₇-cycloalkyl; (C₁-C₄)alkyl; (C₁-C₄)alkyl substituted with one or more(C₁-C₄)alkoxy, halogen, hydroxy, —COOR³³, amino,mono((C₁-C₄)alkyl)amino, di((C₁-C₄)alkyl)amino or (C₆-C₁₀)aryl whereinaryl is optionally substituted with one or more halogen, (C₁-C₄)alkyl,hydroxy, amino, mono((C₁-C₄)alkyl)amino or di((C₁-C₄)alkyl)amino;(C₆-C₁₀)aryl; or (C₆-C₁₀)aryl substituted with one or more halogen,hydroxy, amino, mono((C₁-C₄)alkyl)amino, di((C₁-C₄)alkyl)amino or(C₁-C₄)alkyl;

R²⁶ and R²⁷ independently represent hydrogen, lower alkanoyl, loweralkoxy-lower alkanoyl, aroyl, carbamoyl or mono- or di-loweralkylcarbamoyl; and R³⁰ and R³³ are independently hydrogen,(C₁-C₄)alkyl, (C₆-C₁₀)aryl or (C₆-C₁₀)aryl((C₁-C₄)alkyl); or apharmaceutically acceptable salt thereof.

Additional specific values include compounds wherein at least one of R²⁸and R²⁹ is (C₁-C₄)alkyl substituted with one or more (C₁-C₄)alkoxy,halogen, hydroxy, amino, mono((C₁-C₄)alkyl)amino, di((C₁-C₄)alkyl)aminoor (C₆-C₁₀)aryl wherein aryl is optionally substituted with one or morehalogen, hydroxy, amino, (C₁-C₄)alkyl, R³⁰OOC—(C₁-C₄)alkyl,mono((C₁-C₄)alkyl)amino or di((C₁-C₄)alkyl)amino.

Additional specific values include compounds wherein at least one of R³¹and R³² is C₁₋₄-alkyl substituted with one or more (C₁-C₄)alkoxy,halogen, hydroxy, amino, mono((C₁-C₄)alkyl)amino, di((C₁-C₄)alkyl)aminoor C₆₋₁₀-aryl wherein aryl is optionally substituted with one or morehalogen, hydroxy, amino, (C₁-C₄)alkyl, R³⁰OOC—(C₁-C₄)alkylene-,mono((C₁-C₄)alkyl)amino or di((C₁-C₄)alkyl)amino.

Additional specific values include compounds wherein at least one of R²⁸and R²⁹ is C₆₋₁₀-aryl substituted with one or more halogen, hydroxy,amino, mono((C₁-C₄)alkyl)amino, di((C₁-C₄)alkyl)amino or (C₁-C₄)alkyl.

Additional specific values include compounds wherein at least one of R³¹and R³² is C₆₋₁₀-aryl substituted with one or more halogen, hydroxy,amino, mono((C₁-C₄)alkyl)-mono((C₁-C₄)alkyl)amino or (C₁-C₄)alkyl.

Additional specific values include compounds wherein R³¹ is hydrogen andR³² is (C₁-C₄)alkyl, cyclopropyl or hydroxy-(C₂-C₄)alkyl. A specific R²⁸group is (C₁-C₄)alkyl substituted with (C₆-C₁₀)aryl, that is in turnsubstituted with R³⁰O(O)C—(C₁-C₄)alkylene-.

A specific compound having formula (IV) is:

wherein R³⁰ is hydrogen, methyl, ethyl, n-propyl or isopropyl. Oneembodiment provides a compound wherein the R³⁰ group is methyl or ethyl.In one embodiment, the R³⁰ group is methyl.

Two compounds that can be used in practicing the present invention havethe formula:

wherein R³⁰ is hydrogen (acid, CGS21680) and where R³⁰ is methyl (ester,JR2171).

The compounds of the invention having formula (IV) may be synthesized asdescribed in: U.S. Pat. No. 4,968,697 or J. Med. Chem., 33, 1919-1924,(1990).

Another agonist compound expected to be useful in the present inventionis IB-MECA:

It will be appreciated by those skilled in the art that the compounds offormulas described herein, e.g., (I), (II), (III), and (IV), have morethan one chiral center and may be isolated in optically active andracemic forms. In one embodiment, the riboside moiety of the compoundsis derived from D-ribose, i.e., the 3N,4N-hydroxyl groups are alpha tothe sugar ring and the 2N and 5N groups is beta (3R,4S,2R,5S). When thetwo groups on the cyclohexyl group are in the 1- and 4-position, theyare preferably trans. Some compounds may exhibit polymorphism. It is tobe understood that the present invention encompasses any racemic,optically-active, polymorphic, or stereoisomeric form, or mixturesthereof, of a compound of the invention, which possess the usefulproperties described herein, it being well known in the art how toprepare optically active forms (for example, by resolution of theracemic form by recrystallization techniques, or enzymatic techniques,by synthesis from optically-active starting materials, by chiralsynthesis, or by chromatographic separation using a chiral stationaryphase) and how to determine adenosine agonist activity using the testsdescribed herein, or using other similar tests which are well known inthe art.

It is understood that any embodiment or feature of the present inventionwhether characterized as preferred or not characterized as preferred maybe combined with any other embodiment or feature of the invention,whether such other feature is characterized as preferred or notcharacterized as preferred.

DEFINITIONS

The following definitions are used, unless otherwise described.

The terms “include”, “for example”, “such as”, and the like are usedillustratively and are not intended to limit the present invention.

The indefinite articles “a” and “an” mean “at least one” or “one ormore” when used in this application, including the claims, unlessspecifically indicated otherwise.

A_(2A) agonist refers to an agent that agonizes the Adenosine A_(2A)receptor with a Ki of <1 μM. An A_(2A) agonist may be selective forA_(2A) (e.g., at least 10, 50, or 100/l over another denosine receptorsubtype/A_(2A) receptor). An A_(2A) agonist may also be cross reactivewith other adenosine receptor subtypes (e.g., A₁, A_(2B), and A₃). TheA_(2A) agonist may activate other receptors with a greater or lesseraffinity than the A_(2A) receptor.

It will be appreciated by those skilled in the art that compounds of theinvention having a chiral center may exist in and be isolated inoptically active, and racemic forms. Some compounds may exhibitpolymorphism. It is to be understood that the present inventionencompasses any racemic, optically-active, polymorphic, orstereoisomeric form, or mixtures thereof, of a compound of theinvention, which possess the useful properties described herein; itbeing well known in the art how to prepare optically active forms (forexample, by resolution of the racemic form by recrystallizationtechniques, by synthesis from optically-active starting materials, bychiral synthesis, or by chromatographic separation using a chiralstationary phase) and how to determine therapeutic activity using thestandard tests described herein or using other similar tests which arewell known in the art.

Examples of the molecular weight of compounds useful in the presentinvention can include (a) less than about 500, 550, 600, 650, 700, 750,800, 850, 900, 950, or 1000 grams per mole; (b) less than about 950grams per mole; (c) less than about 850 grams per mole, and, (d) lessthan about 750 grams per mole.

The term “substituted” means that any one or more hydrogens on thedesignated atom is replaced with a selection from the indicated group,provided that the designated atom's normal valency is not exceeded, andthat the substitution results in a stable compound. When a substituentis keto (i.e., ═O), then 2 hydrogens on the atom are replaced. Ketosubstituents are not present on aromatic moieties.

Stable means that the compound is suitable for pharmaceutical use.

The present invention covers stable compound and thus avoids, unlessotherwise specified, the following bond types: heteroatom-halogen, N—S,O—S, O—O, and S—S.

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include tritium anddeuterium. Isotopes of carbon include C-13 and C-14.

“Alkyl” includes both branched and straight-chain saturated aliphatichydrocarbon groups having the specified number of carbon atoms. C₁₋₆alkyl, for example, includes C₁, C₂, C₃, C₄, C₅, and C₆ alkyl groups.Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl.

“Haloalkyl” includes both branched and straight-chain saturatedaliphatic hydrocarbon groups having the specified number of carbonatoms, substituted with 1 or more halogen (for example-C_(v)F_(w) wherev=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are notlimited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, andpentachloroethyl.

“Hydroxyalkyl” includes both branched and straight-chain saturatedaliphatic hydrocarbon groups having the specified number of carbonatoms, substituted with 1 or more hydroxy groups (e.g., 1, 2, or 3OH).Examples of hydroxyl alkyl include hydroxymethyl, hydroxyethyl, andhydroxy-n-propyl.

“Alkoxy” is an alkyl-O-group.

“Alkenyl” includes the specified number of hydrocarbon atoms in eitherstraight or branched configuration with one or more unsaturatedcarbon-carbon bonds that may occur in any stable point along the chain,such as ethenyl and propenyl. C₂₋₆ alkenyl includes C₂, C₃, C₄, C₅, andC₆ alkenyl groups.

“Alkynyl” includes the specified number of hydrocarbon atoms in eitherstraight or branched configuration with one or more triple carbon-carbonbonds that may occur in any stable point along the chain, such asethynyl and propynyl. C₂₋₆ Alkynyl includes C₂, C₃, C₄, C₅, and C₆alkynyl groups.

“Cycloalkyl” includes the specified number of hydrocarbon atoms in asaturated ring, such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl. C₃₋₈ cycloalkyl includes C₃,C₄, C₅, C₆, C₇, and C₈ cycloalkyl groups. Cycloalkyl also includebicycloalkyl and tricycloalkyl, both of which include fused and bridgedrings (e.g., norbornane and adamantane).

“Halo” or “halogen” refers to fluoro, chloro, bromo, and iodo.

“Aryl” refers to any stable 6, 7, 8, 9, 10, 11, 12, or 13 memberedmonocyclic, bicyclic, or tricyclic ring, wherein at least one ring, ifmore than one is present, is aromatic. Examples of aryl includefluorenyl, phenyl, naphthyl, indanyl, and tetrahydronaphthyl.

“Heteroaryl” refers to any stable 5, 6, 7, 8, 9, 10, 11, or 12 membered,(unless the number of members is otherwise recited), monocyclic,bicyclic, or tricyclic heterocyclic ring that is aromatic, and whichconsists of carbon atoms and 1, 2, 3, or 4 heteroatoms independentlyselected from the group consisting of N, O, and S. If the heteroaryl isdefined by the number of carbons atoms, then 1, 2, 3, or 4 of the listedcarbon atoms are replaced by a heteroatom. If the heteroaryl group isbicyclic or tricyclic, then at least one of the two or three rings mustcontain a heteroatom, though both or all three may each contain one ormore heteroatoms. If the heteroaryl group is bicyclic or tricyclic, thenonly one of the rings must be aromatic. The N group may be N, NH, orN-substituent, depending on the chosen ring and if substituents arerecited. The nitrogen and sulfur heteroatoms may optionally be oxidized(e.g., S, S(O), S(O)₂, and N—O). The heteroaryl ring may be attached toits pendant group at any heteroatom or carbon atom that results in astable structure. The heteroaryl rings described herein may besubstituted on carbon or on a nitrogen atom if the resulting compound isstable.

Examples of heteroaryl include acridinyl, azocinyl, benzimidazolyl,benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl,benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl,4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolyl,1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl,isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl,oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl,phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl,phenoxathinyl, phenoxazinyl, phthalazinyl, pteridinyl, pyranyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole,pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, 2H-pyrrolyl, pyrrolyl,quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

“Heterocycle” refers to any stable 4, 5, 6, 7, 8, 9, 10, 11, or 12membered, (unless the number of members is otherwise recited),monocyclic, bicyclic, or tricyclic heterocyclic ring that is saturatedor partially unsaturated, and which consists of carbon atoms and 1, 2,3, or 4 heteroatoms independently selected from the group consisting ofN, O, and S. If the heterocycle is defined by the number of carbonsatoms, then from 1, 2, 3, or 4 of the listed carbon atoms are replacedby a heteroatom. If the heterocycle is bicyclic or tricyclic, then atleast one of the two or three rings must contain a heteroatom, thoughboth or all three may each contain one or more heteroatoms. The N groupmay be N, NH, or N-substituent, depending on the chosen ring and ifsubstituents are recited. The nitrogen and sulfur heteroatoms optionallymay be oxidized (e.g., S, S(O), S(O)₂, and N—O). The heterocycle may beattached to its pendant group at any heteroatom or carbon atom thatresults in a stable structure. The heterocycles described herein may besubstituted on carbon or on a nitrogen atom if the resulting compound isstable.

Examples of heterocycles include, but are not limited to, acridinyl,azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl,naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, andxanthenyl. Also included are fused ring and spiro compounds containing,for example, the above heterocycles.

Mammal and patient covers warm blooded mammals that are typically undermedical care (e.g., humans and domesticated animals). Examples ofmammals include (a) feline, canine, equine, bovine, and human and (b)human.

“Treating” or “treatment” covers the treatment of a disease-state in amammal, and includes: (a) preventing the disease-state from occurring ina mammal, in particular, when such mammal is predisposed to thedisease-state but has not yet been diagnosed as having it; (b)inhibiting the disease-state, e.g., arresting it development; and/or (c)relieving the disease-state, e.g., causing regression of the diseasestate until a desired endpoint is reached. Treating also includes theamelioration of a symptom of a disease (e.g., lessen the pain ordiscomfort), wherein such amelioration may or may not be directlyaffecting the disease (e.g., cause, transmission, expression, etc.).

“Pharmaceutically acceptable salts” refer to derivatives of thedisclosed compounds wherein the parent compound is modified by makingacid or base salts thereof. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include, but are not limited to, thosederived from inorganic and organic acids selected from1,2-ethanedisulfonic, 2-acetoxybenzoic, 2-hydroxyethanesulfonic, acetic,ascorbic, benzenesulfonic, benzoic, bicarbonic, carbonic, citric,edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic,gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic,hydrabamic, hydrobromic, hydrochloric, hydroiodide, hydroxymaleic,hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic,maleic, malic, mandelic, methanesulfonic, napsylic, nitric, oxalic,pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic,propionic, salicyclic, stearic, subacetic, succinic, sulfamic,sulfanilic, sulfuric, tannic, tartaric, and toluenesulfonic.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, Pa.,1990, p 1445, the disclosure of which is hereby incorporated byreference.

“Therapeutically effective amount” includes an amount of a compound ofthe present invention that is effective when administered alone or incombination to a indication listed herein. “Therapeutically effectiveamount” also includes an amount of the combination of compounds claimedthat is effective to treat the desired indication. The combination ofcompounds is preferably a synergistic combination. Synergy, asdescribed, for example, by Chou and Talalay, Adv. Enzyme Regul. 1984,22:27-55, occurs when the effect of the compounds when administered incombination is greater than the additive effect of the compounds whenadministered alone as a single agent. In general, a synergistic effectis most clearly demonstrated at sub-optimal concentrations of thecompounds. Synergy can be in terms of lower cytotoxicity, increasedeffect, or some other beneficial effect of the combination compared withthe individual components.

Specific and preferred values listed for radicals, substituents, andranges, are for illustration only; they do not exclude other definedvalues or other values within defined ranges for the radicals andsubstituents.

The preparation of compounds useful in practicing the present inventionare described in numerous patents and published application, includingU.S. Pat. No. 6,232,297; USAN 2003/0186926; USAN 2006/0217343; USAN2006/0040888; and, USAN 2006/0040889.

The following abbreviations have been used herein:

-   -   2-Aas 2-alkynyladenosines;    -   ATL146e        4-{3-[6-Amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}cyclohexanecarboxylic        acid methyl ester;    -   ATL313        4-{3-[6-Amino-9-(5-cyclopropylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-y-1)-9H-purin-2-yl]-prop-2-ynyl}-piperidine-1-carboxylic        Acid methyl ester (Example 2 of USAN 2006/0040888);    -   CGS21680        2-[4-(2-carboxyethyl)phenethylamino]-5′-N-ethyl-carboxamidoadenosine;    -   C1-IB-MECA        N6-3-iodo-2-chlorobenzyladenosine-5′-N-methyluronamide;    -   NECA 5′-N-ethylcarboxamidoadenosine;    -   IB-MECA N6-3-iodobenzyladenosine-5′-N-methyluronamide;    -   2-Iodoadenosine        5-(6-amino-2-iodo-purin-9-yl)-3,4-dihydroxytetrahydro-furan-2-carboxylic        acid ethylamide    -   INECA 2-iodo-N-ethylcarboxamidoadenosine    -   MRS 1220,        N-(9-chloro-2-furan-2-yl-[1,2,4]triazolo[1,5-c]quinazolin-5-yl)-2-phenylacetamide;    -   NECA N-ethylcarboxamidoadenosine

The compounds of the present invention can be formulated aspharmaceutical compositions and administered to a mammalian host, suchas a human patient in a variety of forms adapted to the chosen route ofadministration, e.g., orally or parenterally, by intravenous,intramuscular, topical, inhalation or subcutaneous routes. Exemplarypharmaceutical compositions are disclosed in “Remington: The Science andPractice of Pharmacy”, A. Gennaro, ed., 20th edition, Lippincott,Williams & Wilkins, Philadelphia, Pa.

Thus, the present compounds may be systemically administered, e.g.,orally, in combination with a pharmaceutically acceptable excipient suchas an inert diluent or an assimilable edible carrier. They may beenclosed in hard or soft shell gelatin capsules, may be compressed intotablets or may be incorporated directly with the food of the patient'sdiet. For oral therapeutic administration, the active compound may becombined with one or more excipients and used in the form of ingestibletablets, buccal tablets, troches, capsules, elixirs, suspensions,syrups, wafers, and the like. Such compositions and preparations shouldcontain at least 0.1% of active compound. The percentage of thecompositions and preparations may, of course, be varied and mayconveniently be between about 2 to about 60% of the weight of a givenunit dosage form. The amount of active compound in such therapeuticallyuseful compositions is such that an effective dosage level will beobtained.

The tablets, troches, pills, capsules, and the like may also contain thefollowing: binders such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, fructose, lactose or aspartame or a flavoring agent such aspeppermint, oil of wintergreen or cherry flavoring may be added. Whenthe unit dosage form is a capsule, it may contain, in addition tomaterials of the above type, a liquid carrier, such as a vegetable oilor a polyethylene glycol. Various other materials may be present ascoatings or to otherwise modify the physical form of the solid unitdosage form. For instance, tablets, pills or capsules may be coated withgelatin, wax, shellac or sugar and the like. A syrup or elixir maycontain the active compound, sucrose or fructose as a sweetening agent,methyl and propylparabens as preservatives, a dye and flavoring such ascherry or orange flavor. Of course, any material used in preparing anyunit dosage form should be pharmaceutically acceptable and substantiallynon-toxic in the amounts employed. In addition, the active compound maybe incorporated into sustained-release preparations and devices.

The active compound may also be administered intravenously orintraperitoneally by infusion or injection. Solutions of the activecompound or its salts can be prepared in water, optionally mixed with anontoxic surfactant. Dispersions can also be prepared in glycerol,liquid polyethylene glycols, triacetin, and mixtures thereof and inoils. Under ordinary conditions of storage and use, these preparationscontain a preservative to prevent the growth of microorganisms.

The pharmaceutical dosage forms suitable for injection or infusion caninclude sterile aqueous solutions or dispersions or sterile powderscomprising the active ingredient which are adapted for theextemporaneous preparation of sterile injectable or infusible solutionsor dispersions, optionally encapsulated in liposomes. In all cases, theultimate dosage form should be sterile, fluid and stable under theconditions of manufacture and storage. The liquid carrier or vehicle canbe a solvent or liquid dispersion medium comprising, for example, water,ethanol, a polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycols, and the like), vegetable oils, nontoxic glycerylesters, and suitable mixtures thereof. The proper fluidity can bemaintained, for example, by the formation of liposomes, by themaintenance of the required particle size in the case of dispersions orby the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, buffers or sodiumchloride. Prolonged absorption of the injectable compositions can bebrought about by the use in the compositions of agents delayingabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the activecompound in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfilter sterilization. In the case of sterile powders for the preparationof sterile injectable solutions, the preferred methods of preparationare vacuum drying and the freeze drying techniques, which yield a powderof the active ingredient plus any additional desired ingredient presentin the previously sterile-filtered solutions.

For topical administration, the present compounds may be applied in pureform, i.e., when they are liquids. However, it will generally bedesirable to administer them to the skin as compositions orformulations, in combination with a dermatologically acceptable carrier,which may be a solid or a liquid.

Useful solid carriers include finely divided solids such as talc, clay,microcrystalline cellulose, silica, alumina and the like. Useful liquidcarriers include water, alcohols or glycols or water-alcohol/glycolblends, in which the present compounds can be dissolved or dispersed ateffective levels, optionally with the aid of non-toxic surfactants.Adjuvants such as fragrances and additional antimicrobial agents can beadded to optimize the properties for a given use. The resultant liquidcompositions can be applied from absorbent pads, used to impregnatebandages and other dressings or sprayed onto the affected area usingpump-type or aerosol sprayers.

Thickeners such as synthetic polymers, fatty acids, fatty acid salts andesters, fatty alcohols, modified celluloses or modified mineralmaterials can also be employed with liquid carriers to form spreadablepastes, gels, ointments, soaps, and the like, for application directlyto the skin of the user.

Examples of useful dermatological compositions which can be used todeliver the compounds of the present invention to the skin are known tothe art; for example, see Jacquet et al. (U.S. Pat. No. 4,608,392),Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157)and Wortzman (U.S. Pat. No. 4,820,508). Useful dosages of the compoundsof the present invention can be determined by comparing their in vitroactivity, and in vivo activity in animal models. Methods for theextrapolation of effective dosages in mice, and other animals, to humansare known to the art; for example, see U.S. Pat. No. 4,938,949.

Generally, the concentration of the compound(s) of the present inventionin a liquid composition, such as a lotion, will be from (a) about 0.1-25wt % and (b) about 0.5-10 wt %. The concentration in a semi-solid orsolid composition such as a gel or a powder will be (a) about 0.1-5 wt %and (b) about 0.5-2.5 wt %.

The amount of the compound or an active salt or derivative thereof,required for use in treatment will vary not only with the particularcompound or salt selected but also with the route of administration, thenature of the condition being treated, and the age and condition of thepatient and will be ultimately at the discretion of the attendantphysician or clinician. In general, however, a suitable dose will be inthe range of from (a) about 1.0-100 mg/kg of body weight per day, (b)about 10-75 mg/kg of body weight per day, and (c) about 5-20 mg perkilogram body weight per day.

The compound can be conveniently administered in unit dosage form; e.g.,tablets, caplets, etc., containing (a) about 4-400 mg, (b) about 10-200mg, and (c) about 20-100 mg of active ingredient per unit dosage form.

Ideally, the active ingredient should be administered to achieve peakplasma concentrations of the active compound of from (a) about 0.02-20μM, (b) about 0.1-10 μM, and (c) about 0.5-5 μM. These concentrationsmay be achieved, for example, by the intravenous injection of a0.005-0.5% solution of the active ingredient, or orally administered asa bolus containing about 4400 mg of the active ingredient.

The compounds of the invention can also be administered by inhalationfrom an inhaler, insufflator, atomizer or pressurized pack or othermeans of delivering an aerosol spray. Pressurized packs may comprise asuitable propellant such as carbon dioxide or other suitable gas. Incase of a pressurized aerosol, the dosage unit may be determined byproviding a value to deliver a metered amount. The inhalers,insufflators, atomizers are fully described in pharmaceutical referencebooks such as Remington's Pharmaceutical Sciences Volumes 16 (1980) or18 (1990) Mack Publishing Co.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations; such as multiple inhalations from an insufflator or byapplication of a plurality of drops into the eye.

All patents, patent applications, books and literature cited in thespecification are hereby incorporated by reference in their entirety. Inthe case of any inconsistencies, the present disclosure, including anydefinitions therein will prevail.

The invention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

EXAMPLES

A mouse model has been enabled in which selective temporary occlusion ofblood flow into the left liver lobe results in a profound accelerationof tumor growth in the clamped liver lobes, but not in the unclampedliver lobes. An A_(2A) receptor agonist was then studied to determineits effect on the accelerated tumor growth.

Detailed Protocol

1. Before the Experiment: Animals

-   -   Male Balb/C mice (10-12 weeks) are housed under standard        laboratory conditions with free access to water and chow and a        12-hour dark-light cycle.

2. Before the Experiment: Cell Culture

-   -   The murine colon carcinoma cell line C26 is cultured in        Dulbecco's modified Eagle's medium supplemented with 5%        heat-inactivated fetal calf serum, penicillin (100 units/ml) and        streptomycin (100 μg/ml) in a 5% carbon dioxide environment.

3. Day 0: Induction of Liver Metastases

-   -   Confluent cultures of the C26 cell line are harvested by brief        trypsinization (0.05 trypsin in 0.02% EDTA).    -   After centrifugation, single cell suspensions are prepared in        PBS to a final concentration of 5×10⁴ cells/100 μl.    -   Cell viability is determined by trypan blue staining, and should        be ≧98%.    -   The induction of liver metastases is performed under inhalation        anesthesia with a 1.5-2% isoflurane/O2 mixture using a mask.    -   Buprenorfine (3 μg/mouse) is administered intramuscularly prior        to surgery to provide sufficient intra- and postoperative        analgesia.    -   Surgical procedures are performed under aseptic conditions.    -   Body temperature is maintained at 36.5-37.5° C. by placing the        animals on a heated table and covering them by aluminium foil.    -   Through a left lateral flank incision, 5×10⁴ C26 colorectal        carcinoma cells are injected into the splenic parenchyma (within        an hour after trypsinisation).    -   After ten minutes, the spleen is removed to prevent intrasplenic        tumor growth.    -   After the procedure a small amount of saline is left in the        abdominal cavity and the peritoneum and skin are separately        closed with 5.0 vicryl.    -   Animals are allowed to recover from anesthesia under standard        laboratory conditions and are allowed free access to water and        chow.

4. Day 0-5:

-   -   Micrometastases are allowed to develop throughout the liver for        5 days.

5. Day 5: Murine Model of Hepatic I/R

-   -   The induction of hepatic I/R is performed under inhalation        anesthesia with a 1.5-2% isoflurane/O2 mixture using a mask.    -   Buprenorfine (3 μg/mouse) is administered intramuscularly prior        to surgery to provide sufficient intra- and postoperative        analgesia.    -   Surgical procedures are performed under aseptic conditions.    -   Body temperature is maintained at 36.5-37.5° C. by placing the        animals on a heated table and covering them by aluminium foil.    -   ATL-313 solutions are prepared and suspended in osmotic        minipumps (Alzet) at a dose of 3 ng/kg/min. Minipumps are placed        in normal saline at 37° C. for at least 4 hours prior to the        operation, to allow immediate drug delivery.    -   After laparotomy, mice receive an intraperitoneal bolus        injection of 1 ng/kg ATL-313.    -   A control group received the A_(2A)R antagonist ZM241385 as an        intraoperative bolus (1 micro-g/kg) and subsequently        continuously using osmotic intraperitoneal minipumps (10        ng/kg/min; 3 days).    -   Sham operated mice undergo laparotomy with exposure of the liver        but without interruption of hepatic flow.    -   Partial hepatic I/R is induced by occluding the vascular inflow        of the left lateral liver lobe for 45 minutes, corresponding to        approximately 40% of the liver mass.    -   Surgical foil is placed over the laparotomy wound to avoid        dehydration.    -   After removal of the clamps a small amount of saline is left in        the abdominal cavity    -   The peritoneum and skin are separately closed with 5.0 vicryl.

6. Day 5-10:

-   -   Micrometastases are allowed to grow out to macrometastases        (approximately 10-20% of the non-clamped lobes at day 10) for 5        days

7. Day 10:

-   -   Livers were harvested, fixed in formalin, and embedded in        paraffin. Tissue sections were stained with H&E and the        following parameters were assessed by an operator who was        blinded to treatment.        -   1. Hepatic Replacement Area: =morphometric assessment of the            % liver tissue that has been replaced by tumor tissue        -   HRA ratios=ratio between HRA values in the ischemic            (clamped) versus the non-ischemic lobes.        -   Necrosis=morphometric assessment of % liver tissue that has            become necrotic.

HRA and necrosis values were assessed on 4 non-sequential H&E-stainedtissue sections by semi-automated stereology (Leica Q-Prodit system,Leica Microsystems, Rijswijk, The Netherlands) using a 4-points gridoverlaid on 100 fields per slide at a magnification of 40×.

All cited publications, patents, and patent documents are incorporatedby reference herein, as though individually incorporated by reference.The invention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

1. A method for treating recurrent tumor metastases following liverresection, comprising: administering to a patient in need thereof atherapeutically effective amount of an A_(2A) adenosine receptoragonist.
 2. The method of claim 1, wherein the agonist is administeredprior to liver resection.
 3. The method of claim 1, wherein the agonistis administered during liver resection.
 4. The method of claim 1,wherein the agonist is administered post liver resection.
 5. The methodof claim 1, wherein the agonist is administered prior to and post liverresection.
 6. The method of claim 1, wherein the agonist comprises: asubstituted 6-amino-9-(tetrahydrofuran-2′-yl)purine, or apharmaceutically acceptable salt thereof.
 7. The method of claim 1wherein the agonist comprises: a6-amino-9-(3′,4′-dihydroxy-tetrahydrofuran-2′-yl)purine substituted atthe 3- and 5′-positions, or a pharmaceutically acceptable salt thereof.8. The method of claim 1, wherein the agonist comprises: a5-[6-amino-2-(3-piperidin-4-yl-prop-1-ynyl)-purin-9-yl]-3,4-dihydroxy-tetrahydro-furan-2-carboxylicacid cyclopropylamide, substituted on the piperidine nitrogen, or apharmaceutically acceptable salt thereof.
 9. The method of claim 1wherein the agonist comprises: a4-{3-[6-amino-9-(5-cyclopropylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}-piperidine-1-carboxylicacid ester or a pharmaceutically acceptable salt thereof.
 10. The methodof claim 1, wherein the agonist comprises: a5-[6-amino-2-(3-piperidin-4-yl-prop-1-ynyl)-purin-9-yl]-3,4-dihydroxy-tetrahydro-furan-2-carboxylicacid ethylamide, substituted on the piperidine nitrogen, or apharmaceutically acceptable salt thereof.
 11. The method of claim 1,wherein the agonist comprises: a4-{3-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}-piperidine-1-carboxylicacid ester or a pharmaceutically acceptable salt thereof.
 12. The methodof claim 1, wherein the A_(2A) adenosine receptor agonist is a compoundof formula I or a stereoisomer or pharmaceutically acceptable saltthereof:

wherein Z^(a) is C≡C, O, NH, or NHN═CR^(3a); Z is CR³R⁴R⁵ or NR⁴R⁵; eachR¹ is independently hydrogen, halo, —OR^(a), —SR^(a), (C₁-C₈)alkyl,cyano, nitro, trifluoromethyl, trifluoromethoxy, (C₃-C₈)cycloalkyl,heterocycle, heterocycle(C₁-C₈)alkylene-, aryl, aryl(C₁-C₈)alkylene-,heteroaryl, heteroaryl(C₁-C₈)alkylene-, —CO₂R^(a), R^(a)C(═O)O—,R^(a)C(═O)—, —OCO₂R^(a), R^(b)R^(c)NC(═O)O—, R^(a)OC(═O)N(R^(b))—,R^(b)R^(c)N—, R^(b)R^(c)NC(═O)—, R^(a)C(═O)N(R^(b)R^(b)R^(c)NC(═O)N(R^(b))—, R^(b)R^(c)NC(═S)N(R^(b))—, —OPO₃R^(a),R^(a)OC(═S)—, R^(a)C(═S)—, —SSR^(a), R^(a)S(═O)—, R^(a)S(═O)₂—, or—N═NR^(b); each R² is independently hydrogen, halo, (C₁-C₈)alkyl,(C₃-C₈)cycloalkyl, heterocycle, heterocycle(C₁-C₈)alkylene-, aryl,aryl(C₁-C₈)alkylene-, heteroaryl, or heteroaryl(C₁-C₈)alkylene-;alternatively, R¹ and R² and the atom to which they are attached is C═O,C═S or C═NR^(d), R⁴ and R⁵ are independently H or (C₁-C₈)alkyl;alternatively, R⁴ and R⁵ together with the atom to which they areattached form a saturated, partially unsaturated, or aromatic ring thatis mono-, bi- or polycyclic and has 3, 4, 5, 6, 7, 8, 9 or 10 ring atomsoptionally having 1, 2, 3, or 4 heteroatoms selected from non-peroxideoxy (—O—), thio (—S—), sulfinyl (—SO—), sulfonyl (—S(O)₂—) or amine(—NR^(b)—) in the ring; wherein R⁴ and R⁵ are independently substitutedwith 0-3 R⁶ groups or any ring comprising R⁴ and R⁵ is substituted withfrom 0 to 6 R⁶ groups; each R⁶ is independently hydrogen, halo, —OR^(a),—SR^(a), (C₁-C₈)alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy,(C₁-C₈)cycloalkyl, (C₆-C₁₂)bicycloalkyl, heterocycle, heterocycle(C₁-C₈)alkylene-, aryl, aryl (C₁-C₈)alkylene-, heteroaryl,heteroaryl(C₁-C₈)alkylene-, —CO₂R^(a), R^(a)C(═O)O—, R^(a)C(═O)—,—OCO₂R^(a), R^(b)R^(c)NC(═O)O—, R^(a)OC(═O)N(R^(b))—, R^(b)R^(c)N—,R^(b)R^(c)NC(═O)—, R^(a)C(═O)N(R^(b))—, R^(b)R^(c)NC(═O)N(R^(b))—,R^(b)R^(c)NC(═S)N(R^(b))—, —OPO₃R^(a), R^(a)OC(═S)—, R^(a)C(═S)—,—SSR^(a), R^(a)S(═O)—, —NNR^(b), or two R⁶ groups and the atom to whichthey are attached is C═O, C═S; or two R⁶ groups together with the atomor atoms to which they are attached can form a carbocyclic orheterocyclic ring comprising from 1-6 carbon atoms and 1, 2, 3, or 4heteroatoms selected from non-peroxide oxy (—O—), thio (—S—), sulfinyl(—SO—), sulfonyl (—S(O)₂—) or amine (—NR^(b)—) in the ring; R³ ishydrogen, halo, —OR^(a), —SR^(a), (C₁-C₈)alkyl, cyano, nitro,trifluoromethyl, trifluoromethoxy, (C₃-C₈)cycloalkyl, heterocycle,heterocycle(C₁-C₈)alkylene-, aryl, aryl(C₁-C₈)alkylene-, heteroaryl,heteroaryl(C₁-C₈)alkylene-, —CO₂R^(a), R^(a)C(═O)O—, R^(a)C(═O)—,—OCO₂R^(b), R^(b)R^(c)NC(═O)O—, R^(a)OC(═O)N(R^(b))—, R^(b)R^(c)N—,R^(b)R^(c)NC(═O)—, R^(a)C(═O)N(R^(b))—, R^(b)R^(c)NC(═O)N(R^(b))—,R^(b)R^(c)NC(═S)N(R^(b))—, —OPO₃R^(a), R^(a)OC(═S)—, R^(a)C(═S)—,—SSR^(a), R^(a)S(═O)—, R^(a)S(═O)₂—, —NNR^(b); or if the ring formedfrom CR⁴R⁵ is aryl or heteroaryl or partially unsaturated then R³ can beabsent; R^(3a) is hydrogen, (C₁-C₈)alkyl, or aryl; each R⁷ isindependently hydrogen, (C₁-C₈)alkyl, (C₃-C₈)cycloalkyl, aryl,aryl(C₁-C₈)alkylene, heteroaryl, or heteroaryl(C₁-C₈)alkylene-; X is—CH₂OR^(a), —CO₂R^(a), —CH₂OC(O)R^(a), —C(O)NR^(b)R^(c), —CH₂SR^(a),—C(S)OR^(a), —CH₂OC(S)R^(a), —C(S)NR^(b)R^(c), or —CH₂N(R^(b))(R^(c));alternatively, X is an aromatic ring of the formula:

each Z¹ is non-peroxide oxy (—O—), S(O)₀₋₂, —C(R⁸)—, or amine (—NR⁸—),provided that at least one Z¹ is non-peroxide oxy (—O—), thio (—S—),sulfinyl (—SO—), sulfonyl (—S(O)₂—) or amine (—NR⁸—); each R⁸ isindependently hydrogen, (C₁-C₈)alkyl, (C₁-C₈)alkenyl, (C₃-C₈)cycloalkyl,(C₃-C₈)cycloalkyl(C₁-C₈)alkylene, (C₃-C₈)cycloalkenyl,(C₃-C₈)cycloalkenyl(C₁-C₈)alkylene, aryl, aryl(C₁-C₈)alkylene,heteroaryl, or heteroaryl(C₁-C₈)alkylene, wherein any of the alkyl oralkenyl groups of R⁸ are optionally interrupted by —O—, —S—, or—N(R^(a))—; wherein any of the alkyl, cycloalkyl, heterocycle, aryl, orheteroaryl, groups of R¹, R², R³, R^(3a), R⁶, R⁷ and R⁸ is optionallysubstituted on carbon with one or more (e.g. 1, 2, 3, or 4) substituentsselected from the group consisting of halo, —OR^(a), —SR^(a),(C₁-C₈)alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy,(C₃-C₈)cycloalkyl, (C₆-C₁₂)bicycloalkyl, heterocycle,heterocycle(C₁-C₈)alkylene-, aryl, aryloxy, aryl(C₁-C₈)alkylene-,heteroaryl, heteroaryl(C₁-C₈)alkylene-, —CO₂R^(a), R^(a)C(═O)O—,R^(a)C(═O)—, —OCO₂R^(a), R^(b)R^(c)NC(═O)O—, R^(a)OC(═O)N(R^(b))—,R^(b)R^(c)N—, R^(b)R^(c)NC(═O)—, R^(a)C(═O)N(R^(b))—,R^(b)R^(c)NC(═O)N(R^(b))—, R^(b)R^(c)NC(═S)N(R^(b))—, —OPO₃R^(a),R^(a)OC(═S)—, R^(a)C(═S)—, —SSR^(a), R^(a)S(═O)_(p)—,R^(b)R^(c)NS(O)_(p)—, and —N═NR^(b); wherein any (C₁-C₈)alkyl,(C₃-C₈)cycloalkyl, (C₆-C₁₂)bicycloalkyl, (C₁-C₈)alkoxy, (C₁-C₈)alkanoyl,(C₁-C₈)alkylene, or heterocycle, is optionally partially unsaturated;each R^(a), R^(b) and R^(c) is independently hydrogen, (C₁-C₁₂)alkyl,(C₁-C₈)alkoxy, (C₁-C₈)alkoxy-(C₁-C₁₂)alkylene, (C₃-C₈)cycloalkyl,(C₃-C₈)cycloalkyl-(C₆-C₁₂)alkylene, (C₁-C₈)alkylthio, amino acid, aryl,aryl(C₁-C₈)alkylene, heterocycle, heterocycle-(C₁-C₈)alkylene,heteroaryl, or heteroaryl(C₁-C₈)alkylene; alternatively R^(b) and R^(c),together with the nitrogen to which they are attached, form apyrrolidino, piperidino, morpholino, or thiomorpholino ring; wherein anyof the alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl groups ofR^(a), R^(b) and R^(c) is optionally substituted on carbon with 1 or 2substituents selected from the group consisting of halo,—(CH₂)_(a)OR^(e), —(CH₂)_(a)SR^(e), (C₁-C₈)alkyl, (CH₂)_(a)CN,(CH₂)_(a)NO₂, trifluoromethyl, trifluoromethoxy, —(CH₂)_(a)CO₂R³,(CH₂)_(a)NR^(e)R^(e), and (CH₂)_(a)C(O)NR^(e)R^(e); R^(d) is hydrogen or(C₁-C₆)alkyl; R^(e) is independently selected from H and (C₁-C₆)alkyl; ais 0, 1, or 2; i is 1 or 2 m is 0 to 8; and p is 0 to 2; provided that mis at least 1 when Z is NR⁴R⁵; or a pharmaceutically acceptable saltthereof.
 13. The method of claim 9, wherein the A_(2A) adenosinereceptor agonist is a compound selected from the compounds of thefollowing table or a stereoisomer or pharmaceutically acceptable saltthereof:

Ex. # R^(c) R⁷ —(R¹)_(m)—Z
 1. Et H


2. Et H


3. cPr H


4. Et H


5. cPr H


6. Et H


7. cPr H


8. Et H


9. Et H


10. Et H


11. Et H


12. cPr H


13. Et H


14. cPr H


15. Et H


16. cPr H


17. cPr H


18. Et H


19. cPr H


20. Et H


21. cPr H


22. Et H


23. Et H


24. cPr H


25. Et H


26. Et H


27. Et H


28. Et H


29. Et H


30. Et H


31. cPr H


32. Et H


33. Et H


34. cPr H


35. cPr H


36. Et H


37. cPr H


38. Et H


39. cPr H


40. Et H


41. cPr H


42. Et H

*signifies the point of attachment.


14. The method of claim 1, wherein the A_(2A) adenosine receptor agonistis a compound of formula II or a stereoisomer or pharmaceuticallyacceptable salt thereof:

wherein: R¹ and R² independently are selected from the group consistingof H, (C₁-C₈)alkyl, (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₈)alkylene,aryl, aryl(C₁-C₈)alkylene, heteroaryl, heteroaryl(C₁-C₈)alkylene-,diaryl(C₁-C₈)alkylene, and diheteroaryl(C₁-C₈)alkylene, wherein the aryland heteroaryl rings are optionally substituted with 1-4 groupsindependently selected from fluoro, chloro, iodo, bromo, methyl,trifluoromethyl, and methoxy; each R independently is selected from thegroup consisting of H, C₁-C₄ alkyl, cyclopropyl, cyclobutyl, and(CH₂)_(a)cyclopropyl; X is CH or N, provided that when X is CH then Zcannot be substituted with halogen, C₁-C₆ alkyl, hydroxyl, amino, ormono- or di-(C₁-C₆-alkyl)amino; Y is selected from the group consistingof O, NR¹, —(OCH₂CH₂O)_(m)CH₂—, and —(NR¹CH₂CH₂O)_(m)CH₂—, provided thatwhen Y is O or NR¹, then at least one substituent is present on Z; Z isselected from the group consisting of 5-membered heteroaryl, 6-memberedaryl, 6-membered heteroaryl, carbocyclic biaryl, and heterocyclicbiaryl, wherein the point of attachment of Y to Z is a carbon atom on Z,wherein Z is substituted with 0-4 groups independently selected from thegroup consisting of F, Cl, Br, I, (C₁-C₄)alkyl, —(CH₂)_(a)OR³,—(CH₂)_(a)NR³R³, —NHOH, —NR³NR³R³, nitro, —(CH₂)_(a)CN, (CH₂)_(a)CO₂R³,—(CH₂)_(a)CONR³R³, trifluoromethyl, and trifluoromethoxy; alternatively,Y and Z together form an indolyl, indolinyl, isoindolinyl,tetrahydroisoquinolinyl, or tetrahydroquinolinyl moiety wherein thepoint of attachment is via the ring nitrogen and wherein said indolyl,indolinyl, isoindolinyl, tetrahydroisoquinolinyl, ortetrahydroquinolinyl moiety, which is substituted with 0-4 groupsindependently selected from the group consisting of F, Cl, Br, I, C₁-C₄alkyl, —(CH₂)_(a)OR³, —(CH₂)_(a)NR³NR³R³, —NHOH, —NR³NR³R³, NO₂,—(CH₂)_(a)CN, —(CH₂)_(a)CO₂R³, —(CH₂)_(a)CONR³R³, CF₃, and OCF₃; R³ isindependently selected from the group consisting of H, (C₁-C₆)alkyl,cycloalkyl, aryl, and heteroaryl; R⁴ is selected from the groupconsisting of CH₂OR, C(O)NRR, and CO₂R; R⁵ is selected from the groupconsisting of CH₂CH₂, CH═CH, and C≡C; a is selected from 0, 1, and 2; mis selected from 1, 2, and 3; n is selected from 0, 1, and 2; each pindependently is selected from 0, 1, and 2; and, q is selected from 0,1, and
 2. 15. The method of claim 11, wherein the A_(2A) adenosinereceptor agonist is a compound selected from the compounds of thefollowing table or a stereoisomer or pharmaceutically acceptable saltthereof: i

ii

iii

R⁴=A: CH₂OH; B: C(O)NEthyl; C: C(O)NCyclopropyl; Compounds are offormula (i), unless indicated. Ex. # R⁴ Z′  1 C

 2 C

 3 C

 4 A

 5 C

 6 A

 7 A

 8 C

 9 C

10 C

11 A

12 A

13 A

14 C

15 B

16 B

17 C

18 C

19 B

20 C

21 C

22 C

23 C

24 B

25 B

26 B

27 A

28 A

29 A

30 A

31 B

32 B

33 B

34 B

35 A

36 A

37(iii) B

38(iii) C

39(iii) C

40(iii) C

41(iii) C

42 C

43(ii) C

44(ii) A

45(ii) A

46(ii) A

47(ii) C

48(ii) C

49 B

50 B

51 C

52 C

53 A

54 A

55 A

56 C

57 C


16. The method of claim 1, wherein the A_(2A) adenosine receptor agonistis a compound of formula (Ib)-(Id) or a pharmaceutically acceptable saltthereof:


17. The method of claim 1, wherein the A_(2A) adenosine receptor agonistis selected from:

or a pharmaceutically acceptable salt thereof.
 18. The method of claim1, wherein the A_(2A) adenosine receptor agonist is a compound of thefollowing formula or a pharmaceutically acceptable salt thereof:


19. The method of claim 1, wherein the A_(2A) adenosine receptor agonistis a compound of the following formula or a pharmaceutically acceptablesalt thereof: